STAT Mediated TGF-a/EGFR Signaling in squamous cell carcinomas of the head & neck

头部鳞状细胞癌中 STAT 介导的 TGF-a/EGFR 信号转导

基本信息

批准号：
8114193
负责人：
Jennifer Rubin Grandis
金额：
$ 26.98万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8114193
关键词：
Address Antineoplastic Agents Cancer Patient Cetuximab Clinical Epidermal Growth Factor Receptor FDA approved Funding Goals Grant Growth Growth Factor Receptors Head and Neck Neoplasms Head and Neck Squamous Cell Carcinoma Laboratories Malignant Neoplasms Mediating Monoclonal Antibodies Oncogenic Outcome Pathway interactions Patients Pharmaceutical Preparations Pre-Clinical Model Property Proteins Publications Receptor Inhibition Receptor Signaling Regimen Regulatory Pathway Reporting Resistance Role STAT protein STAT1 gene STAT3 gene STAT5A gene Signal Transduction Squamous cell carcinoma Testing Therapeutic Tissues Variant autocrine cohort design epidermal growth factor receptor VIII improved in vitro activity in vivo mutant novel public health relevance receptor receptor expression receptor function resistance mechanism response src-Family Kinases therapy resistant treatment strategy tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) is upregulated in squamous cell carcinomas of the head and neck (SCCHN) where EGFR expression levels in the tumor correlate with decreased survival. The EGFR monoclonal antibody, cetuximab, was FDA-approved in 2006 for the treatment of SCCHN and is the first new drug for this cancer in 45 years. However, despite the ubiquitous expression of EGFR in SCCHN tumors, the clinical response rate to cetuximab as single agent therapy is limited, underscoring the importance of elucidating the mechanisms of persistent tumor growth in the setting of EGFR blockade. We have accumulated extensive evidence that EGFR-mediated activation of selected Signal Transducers and Activators of Transcription (STATs) and Src family kinases contribute to SCCHN growth and survival. We recently reported that a mutant EGFR, EGFRvIII is expressed in up to 40% of SCCHN where EGFRvIII is associated with therapeutic resistance, including resistance to cetuximab. Therefore, we propose to test the overall hypothesis that the loss of growth control in SCCHN is mediated by aberrant EGFR signaling though both mutant and wild-type receptors involving selective activation of STAT proteins and/or Src kinases, with the ultimate aim of designing novel treatment strategies to target these pathways. To accomplish the goals of this proposal, we will: 1) determine the role of Src kinases in EGFR-mediated and EGFR-independent growth pathways in SCCHN; 2) elucidate the contribution of STAT5 activation to SCCHN progression and response to EGFR blockade; and 3) determine the role of STAT and Src signaling in mediating the oncogenic properties of EGFRvIII in SCCHN. PUBLIC HEALTH RELEVANCE: The proposed studies will elucidate the mechanisms of resistance to EGFR targeting strategies in preclinical models of squamous cell carcinoma of the head and neck. In addition, we will test the hypothesis that STATs, Src family kinases and EGFRvIII contribute to cetuximab resistance in 2 SCCHN patient cohorts.

描述（由申请人提供）：表皮生长因子受体（EGFR）在头颈鳞状细胞癌（SCCHN）中上调，其中肿瘤中的EGFR表达水平与生存率降低相关。 EGFR单克隆抗体西妥昔单抗于2006年获得FDA批准用于治疗SCCHN，是45年来第一个治疗这种癌症的新药。然而，尽管 EGFR 在 SCCHN 肿瘤中普遍表达，但西妥昔单抗作为单药治疗的临床反应率有限，这强调了阐明 EGFR 阻断背景下肿瘤持续生长机制的重要性。我们已经积累了大量证据，表明 EGFR 介导的选定信号转导器和转录激活剂 (STAT) 以及 Src 家族激酶的激活有助于 SCCHN 的生长和存活。我们最近报道了突变型 EGFR，EGFRvIII 在高达 40% 的 SCCHN 中表达，其中 EGFRvIII 与治疗耐药性相关，包括对西妥昔单抗的耐药性。因此，我们建议测试以下总体假设：SCCHN 中生长控制的丧失是由异常 EGFR 信号转导介导的，突变型和野生型受体均涉及 STAT 蛋白和/或 Src 激酶的选择性激活，最终目的是设计新的针对这些途径的治疗策略。为了实现本提案的目标，我们将： 1）确定 Src 激酶在 SCCHN 中 EGFR 介导和 EGFR 独立生长途径中的作用； 2) 阐明STAT5激活对SCCHN进展的贡献以及对EGFR阻断的反应； 3) 确定 STAT 和 Src 信号传导在 SCCHN 中介导 EGFRvIII 致癌特性中的作用。公共健康相关性：拟议的研究将阐明头颈部鳞状细胞癌临床前模型对 EGFR 靶向策略的耐药机制。此外，我们将测试 STAT、Src 家族激酶和 EGFRvIII 导致 2 个 SCCHN 患者队列中西妥昔单抗耐药性的假设。